Using a genetic approach with the fruit fly Drosophila melanogaster, we have found that the gene twinstar (tsr), which encodes the Drosophila homologue of the actin-binding protein cofilin/ADF, has a physiological role in the eye, as tsr has a light-dependent retinal degeneration (RD) mutant phenotype. We believe tsr represents a large group of genes that are required for viability that have an unidentified RD mutant phenotype. To test this, an RNAi screen for RD mutants in the fly was started. Preliminary data shows that this approach will be successful. The goal of this proposal is to screen 8,000 RNAi inducible lines for an RD mutant phenotype. Once identified, the new RD mutants will be characterized to determine the earliest visible defect in the retina, if the RD is light dependent, and if the degeneration is apoptotic or necrotic. There is significant overlap between RD genes in the fly and humans, indicating common function. Identifying additional Drosophila RD mutants will mark the human homologues as candidates for being associated with retinal diseases. It is also likely that many of the RD genes will have interesting biological functions in the Drosophila eye. Identifying these new RD genes will bring new researchers into the field of RD, leading to a better understanding of vision and retinal disease. PUBLIC HEALTH RELEVANCE: Recent studies in Drosophila have shown that mutants of many genes that cause retinal degeneration in the fly also cause retinal degeneration in humans, suggesting a common function. This grant proposes a genetic screen to identify additional genes in Drosophila that have a retinal degeneration mutant phenotype. Characterizing the roles and molecular functions of these genes will add to an understanding of vision and retinal disease.